Abstract 265: Reduced Aortic Wall Motion and Cyclic Strain in a Williams-Beuren Syndrome Mouse Model Due to Changes in Vessel Structure
Williams-Beuren Syndrome (WBS) is caused by a heterozygous 1.5Mbp deletion of 25 genes. WBS includes supravalvar aortic stenosis and other cardiovascular abnormalities due to loss of one copy of the elastin gene (ELN). We assessed the hypothesis that genetic changes in a WBS mouse model would alter ELN expression, vessel structure, and abdominal aortic wall dynamics in vivo. Using a CreloxP strategy, two half-deletion mouse strains were developed dissecting the critical WBS region. Crossing deletion heterozygotes generates offspring with 4 distinct genotypes (wild type WT, proximal deletion Pd, distal Dd, distal+proximal DP), with the ELN gene falling in the distal deletion. Total RNA from the thorax of 8-day-old mice was isolated and the level of ELN transcription was determined by real-time RT-PCR. On average, ELN levels in Pd mice were similar to WT, while ELN levels in Dd (n=4) and DP (n=5) mice showed reductions of 34% and 25%, respectively. We used M-mode ultrasound to quantify abdominal aortic wall motion throughout the cardiac cycle (n=10 for each genotype). Pulsatile wall motion was resolved using a small-animal ultrasound system and a high-frequency transducer (40MHz). Anterior wall motion was significantly less in Dd and DP mice compared to WT and Pd groups (p<0.001) even after normalization with aortic diameter (WT=10.8±2.2%, Pd=11.± 2.4%, Dd=6.2±1.0%, DP=5.9±2.0%). Circumferential cyclic strain (WT=13.9±2.5%, Pd=14.5±2.7%, Dd=9.0±1.4%, DP=8.8±2.0%) also significantly decreased in Dd and DP mice (p<0.001). Pressure perfusion fixed sections with von Gieson’s staining showed disorganized and thinner elastin sheets in Dd and DP mice (n=4 for each genotype). The reduction in elastin sheet thickness was significant (p<0.001) for Dd and DP mice (WT=3.2±0.5μm, Pd=3.3±0.6μm, Dd=1.5±0.4μm, DP=1.3±0.3μm). In conclusion, heterozygous mice that carry a deletion of the ELN gene (Dd and DP mice) have a less compliant aorta, likely due to reduced ELN transcription and morphological changes in wall structure. This is the first time the mechanical properties of the abdominal aorta in genetically modified mice have been studied in vivo, and provides further insight into the genetic relationship between WBS and aortic compliance.